Hepatitis C is a viral disease that causes inflammation of the liver that may lead to cirrhosis, primary liver cancer and other long-term complications. Synthetic nucleosides are a well-recognized class of compounds shown to be effective against a variety of viral infections, including hepatitis B, HIV, and herpes. Several synthetic nucleosides are reported to inhibit hepatitis C virus (HCV) replication, including ribavirin, which currently is marketed as a drug combination with various forms of interferon. The nucleosides are prodrugs that need to be converted to the biologically active corresponding nucleoside 5′-triphosphate (NTP) in a sequential three-step activation process inside cells by various intracellular kinases. The first step, i.e. conversion of the nucleoside to the 5′-monophosphate (NMP), is generally the slowest step and involves a nucleoside kinase, which is encoded by either the virus or host. Conversion of the NMP to the NTP is generally catalyzed by host nucleotide kinases. The NTP interferes with viral replication through inhibition of HCV NS5B polymerase, an RNA-dependent RNA polymerase (RdRp), and/or via incorporation into a growing strand of RNA followed by chain termination. Since the rate and efficiency of NTP formation are dependent upon structure of each nucleoside, virus genetic make-up, and host cell environment, antiviral activity of a synthetic nucleoside is determined by intrinsic activity of the NTP, NTP half-life, and the nucleoside activation efficiency in a cell.
Natural nucleosides and nucleotides are building blocks of RNA and DNA, and are essential elements for life. Among others they play important roles in DNA replication, cell signaling, and metabolism. Synthetic nucleosides are close analogs of natural nucleosides and are used as antiviral and anticancer agents by taking advantages of the RNA/DNA chain termination property. As a result, identification of compounds that selectively inhibit viral or cancer cell proliferation from normal cells can be challenging.
Nucleosides are hydrophobic molecules with multiple polar functional groups that often contribute to poor oral bioavailability due to poor permeability at gastrointestinal tract, although certain nucleosides such as ribavirin can be moderately absorbed at gastrointestinal tract via transporters. Most synthetic nucleoside analog drugs need a lipophilic moiety to mask the polar functional groups, which adds another layer of prodrug activation of a drug.
The diverse biological functions of nucleosides and the complexity of multiple layers cell-dependent prodrug activation make the development of nucleoside analogs for HCV treatment a substantial challenge. First generation nucleoside-based HCV NS5B polymerase inhibitors were simple ester prodrugs designed to provide oral bioavailability. For example, NM283, R1626, and R7128 were orally available nucleoside prodrugs but failed to adequately address other challenges of nucleoside-based prodrugs. Both R1626 and NM283 demonstrated clinical efficacy in HCV infected patients in phase II clinical trials but also encountered safety issues presumably due to non-discriminate distribution and activation of the nucleosides. R7128 faced a different challenge in clinic where its efficacy is significantly compromised due to the slow conversion of the nucleoside to the active nucleotides.
Second generation nucleoside-based prodrugs of HCV NS5B polymerase inhibitors were designed to deliver nucleoside 5′-monophosphates to improve the efficiency of nucleoside activation in the cells.
Certain other phosphate prodrugs are disclosed in U.S. Pat. No. 8,063,025, U.S. Pat. No. 7,666,855, and PCT Pub. No. WO2009/073506.